Erythromycins, and in particular erythromycin A, are clinically useful, broad-spectrum macrolide antibiotics produced by the gram-positive bacterium Saccharopclyspora erythraea (formerly Streptomyces erythreus). However, a major drawback of erythromycins is their poor acid stability, which can result in diminished and erratic oral absorption.
Numerous erythromycin derivatives have been chemically synthesized in an attempt to produce compounds with improved acid stability without loss of antibacterial activity. (9S)9-Dihydroerythromycin A (which carries a 9-hydroxy group in place of the 9-keto group) has been described (Wiley et al., J. Amer. Chem. Soc., 77:3676-3677 (1955)). Erythromycylamine and erythromycin oxime in which the 9-keto group is replaced, respectively, by an amino or oxime group have also been described (GB 1 100 504; Massey et al, Tetrahedron Letters, 2:157-160 (1970)), as have various erythromycin oxime ethers (U.S. Pat. No. 3,681,326, U.S. Pat. No. 3,869,445 and U.S. Pat. No. 4,063,014). 6-O-methylerythromycin (clarithromycin) and 6,11-di-O-methyl-erythromycin A are described U.S. Pat. No. 4,743,593.
Although the above derivatives exhibit improved acid stability, the synthetic methods by which they are produced are expensive and can produce low yields. Moreover, the acid instability of the starting material (i.e., erythromycin) has hampered efforts to synthesize more active derivatives.
There is therefore a need for improved acid-stable erythromycin derivatives and, moreover, for derivatives which are microbially produced and which thereby circumvent the inefficiency of the aforementioned synthetic methods or at least provide a more favorable starting material for the preparation of synthetic derivatives.